rs17075

Positions:

• chr11-119088621-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000190.4(HMBS):​c.88-14G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.56 in 1,605,040 control chromosomes in the GnomAD database, including 256,196 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.61 (29024 hom., cov: 31)
  • Exomes 𝑓: 0.55 (227172 hom.)
• Consequence: HMBS NM_000190.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.286

Genes affected

HMBS (HGNC:4982): (hydroxymethylbilane synthase) This gene encodes a member of the hydroxymethylbilane synthase superfamily. The encoded protein is the third enzyme of the heme biosynthetic pathway and catalyzes the head to tail condensation of four porphobilinogen molecules into the linear hydroxymethylbilane. Mutations in this gene are associated with the autosomal dominant disease acute intermittent porphyria. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 11-119088621-G-A is Benign according to our data. Variant chr11-119088621-G-A is described in ClinVar as [Benign]. Clinvar id is 255487.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-119088621-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.745 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HMBS	NM_000190.4	c.88-14G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000652429.1	NP_000181.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HMBS	ENST00000652429.1	c.88-14G>A		splice_polypyrimidine_tract_variant, intron_variant			NM_000190.4	ENSP00000498786	P3

Frequencies

GnomAD3 genomes AF: 0.608 AC: 92329 AN: 151916 Hom.: 28992 Cov.: 31

Gnomad AFR AF: 0.752

Gnomad AMI AF: 0.637

Gnomad AMR AF: 0.680

Gnomad ASJ AF: 0.569

Gnomad EAS AF: 0.283

Gnomad SAS AF: 0.501

Gnomad FIN AF: 0.459

Gnomad MID AF: 0.589

Gnomad NFE AF: 0.561

Gnomad OTH AF: 0.604

GnomAD3 exomes AF: 0.560 AC: 140916 AN: 251432 Hom.: 41198 AF XY: 0.552 AC XY: 75037 AN XY: 135888

Gnomad AFR exome AF: 0.752

Gnomad AMR exome AF: 0.725

Gnomad ASJ exome AF: 0.574

Gnomad EAS exome AF: 0.278

Gnomad SAS exome AF: 0.513

Gnomad FIN exome AF: 0.468

Gnomad NFE exome AF: 0.557

Gnomad OTH exome AF: 0.569

GnomAD4 exome AF: 0.555 AC: 805838 AN: 1453006 Hom.: 227172 Cov.: 31 AF XY: 0.553 AC XY: 399884 AN XY: 723366

Gnomad4 AFR exome AF: 0.754

Gnomad4 AMR exome AF: 0.720

Gnomad4 ASJ exome AF: 0.571

Gnomad4 EAS exome AF: 0.268

Gnomad4 SAS exome AF: 0.518

Gnomad4 FIN exome AF: 0.471

Gnomad4 NFE exome AF: 0.558

Gnomad4 OTH exome AF: 0.561

GnomAD4 genome AF: 0.608 AC: 92412 AN: 152034 Hom.: 29024 Cov.: 31 AF XY: 0.602 AC XY: 44729 AN XY: 74302

Gnomad4 AFR AF: 0.752

Gnomad4 AMR AF: 0.679

Gnomad4 ASJ AF: 0.569

Gnomad4 EAS AF: 0.283

Gnomad4 SAS AF: 0.501

Gnomad4 FIN AF: 0.459

Gnomad4 NFE AF: 0.561

Gnomad4 OTH AF: 0.603

Alfa AF: 0.583 Hom.: 27519

Bravo AF: 0.631

Asia WGS AF: 0.416 AC: 1444 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Acute intermittent porphyria Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	6.6
DANN	Benign	0.64
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs17075; hg19: chr11-118959331; COSMIC: COSV53828568; COSMIC: COSV53828568;